Cores for technetium radiopharmaceuticals

ABSTRACT

Novel complexes of technetium ( 99  Tc or  99m  Tc) which contain the moiety Tc═NR, Tc--N═NY or Tc(--N═NY) 2 , and a ligand which confers biological target-seeking properties on the complex, wherein R represents an aryl group, a substituted or unsubstituted alkyl group, or the grouping ═NR 1  R 2  ; Y represents an aryl group or a substituted or unsubstituted alkyl group; and R 1  and R 2  are hydrogen, aryl groups or substituted or unsubstituted aliphatic or cyclic alkyl groups, and may be both the same or different, provided that both are not hydrogen. The complexes are suitable for use in radiopharmaceuticals for a variety of clinical applications. Methods for the preparation of these technetium complexes are also described.

This application is a continuation of now abandoned application Ser. No.07/689,763, filed May 29, 1991.

This invention relates to novel complexes of technetium (Tc), containingthe moiety Tc═NR, Tc--N═NY or Tc(--N═Ny)₂, and their use inradiopharmaceuticals for a variety of clinical applications. Methods forthe preparation of the technetium complexes are also described.

Radiopharmaceuticals may be used as diagnostic or therapeutic agents byvirtue of the physical properties of their constituent radionuclides.Thus, their utility is not based on any pharmacologic action. Mostclinically used drugs of this class are diagnostic agents incorporatinga gamma-emitting nuclide which, because of physical or metabolicproperties of its co-ordinated ligands, localises in a specific organafter intravenous injection. The resultant images can reflect organstructure or function. These images are obtained by means of a gammacamera that detects the distribution of ionising radiation emitted bythe radioactive molecules. The principal isotope currently used inclinical diagnostic nuclear medicine is metastable technetium-99m(^(99m) Tc) and which has a half-life of 6 hours.

The preparation of ^(99m) Tc radiopharmaceuticals generally requiresaddition of generator-produced Na^(99m) TcO₄ eluate to a ligand orligands in the presence of a reducing agent. Many reducing agents havebeen used to this effect including tin metal, stannous ion, sodiumborohydride, ferrous ascorbate, ferrous ion and formamidine sulphonicacid. These procedures often lead to Tc complexes containing the Tc═Omoiety, where the technetium is in the +4 or +5 oxidation state. Theformation of such radiopharmaceutical complexes can often occur viasubstitution reactions on [Tc^(V) OX₅ ]²⁻ or [Tc^(IV) X₆ ]²⁻ molecules,which has been identified as a route of significant synthetic utility(Deutsch E, Libson K, Jurisson S, Lindoy L F, Technetium Chemistry andTechnetium Radiopharmaceuticals, Prog. Inorg. Chem. (1982) 30 p 175).Only under harsh reaction conditions in the presence of powerfulreducing agents and/or strong acids or bases are Tc^(I) oxidation statecomplexes attained and stabilised. A limitation to the formation ofnovel radiopharmaceutical products is the tendency towards formation ofTc═O species, but in addition formation of Tc⁴⁺ or Tc⁵⁺ complexes alsolimits the number and/or type of ligands prone to bind to the metal.

PCT Application W0 85/03063 describes the synthesis of the Tc═N moietyas an intermediate in the preparation of radiopharmaceuticals by virtueof its ability to undergo various ligand substitution reactions. TheTc═N core is again primarily based on the +5 oxidation state of Tc.

The reaction of TcCl₆ ²⁻ with hydroxylamine salts under a variety ofconditions to form a variety of complexes containing the Tc-NO moietyhas been described (Eakins, JCS (1963) 6012; Radnovich and Hoard, J.Phys. Chem. 88 (26) (1984) 6713; Armstrong and Taube, Inorg. Chem.(1976) 15 (3), 1904). This literature is concerned with ⁹⁹ Tc and notwith its metastable isotope ^(99m) Tc. ⁹⁹ Tc has a half-life of 2.1×10⁵years, decays by emitting beta particles, and is of no interest as aradiopharmaceutical.

European Patent Application No. 0 291 281 A describes technetiumcomplexes containing the ^(99m) Tc-NO moiety, together with a ligandwhich confers biological target-seeking properties on the complex, andtheir use as radiopharmaceuticals. The complexes are made frompertechnetate (TcO₄ ⁻) by a variety of routes involving hydroxylaminesalts. Studies of the coordination chemistry of technetium havegenerally been directed towards the synthesis and development of new^(99m) Tc labelled radiopharmaceuticals. ¹ The majority of thetechnetium containing radiopharmaceuticals currently in clinical useinvolve technetium complexes containing either a mono-oxo or di-oxocore, i.e. [Tc^(V) ═O]³⁺ or [Tc^(V) O₂ ]⁺ respectively.¹,2 Technetium(V) oxo-species are used to image kidney, liver, brain and bone tissues.

The terminal imido (2-) moiety, ═NR, is formally isoelectronic to aterminal oxo (2-) function, ═O. Many transition metal complexescontaining an organo-imido ligand are known³. Examples include thefollowing complexes based on rhenium ⁴,5,6, (I, II), tungsten⁷ (III),vanadium⁸ (IV) and molybdenum⁹ (V): ##STR1## where Ar is an aryl group.

When the R substituent of a terminal imide ligand is a dialkyl amidemoiety, NY₂, the imide ligand is more often described as a hydrazide(2-) ligand. Thus the terminal hydrazido (2-) moiety, ═N --NR₂, is alsoisoelectronic to a terminal oxo (2-) function, and many transition metalcomplexes containing hydrazido (2-) ligands are known¹⁰. Examples ofisostructural metal-oxo and metal-hydrazido 2-1 complexes include thefollowing¹¹,12,13,14 : ##STR2##

Similarly, the diazenido moiety, --N═NR, is isoelectronic andisostructural with the nitrosyl ligand (--NO).

Unlike oxo- and nitrosyl ligands, however, imide (2-), hydrazido (2-)and diazenido ligands can carry a variety of different substitutents onthe nitrogen atom which is not bound to the metal atom. The presence ofany of these three moieties in a technetium complex therefore permitsthe preparation of new radiopharmaceuticals with a variety of biologicalcharacteristics which can be modulated by varying or altering the Rsubstituents. In addition, the methods for the synthesis of complexescontaining Tc═NR, Tc═N--NY₂ or Tc--N═NY moieties are compatible with theconcomitant ligation of a wide variety of other ligands. It is thisdiscovery which forms the basis of the present invention.

According to this invention there is provided a complex of technetium(⁹⁹ Tc or ^(99m) Tc) which contains the moiety Tc═NR, Tc--N═NY orTc(--N═NY)₂, and a ligand which confers biological target-seekingproperties on the complex,

wherein

R represents an aryl group, a substituted or unsubstituted alkyl group,or the grouping ═-NR¹ R² ;

Y represents an aryl group or a substituted or unsubstituted alkylgroup; and

R¹ and R² are hydrogen, aryl groups or substituted or unsubstitutedaliphatic or cyclic alkyl groups, and may be both the same or different,provided that both are not hydrogen.

The complex is useful as a radiopharmaceutical.

Complexes in accordance with this invention have the formulae:

    L.sub.n Tc═NR; L.sub.n Tc--N═NY or L.sub.n Tc(--N═NY).sub.2

wherein

L represents a mono- or multi-dentate ligand;

n is 1, 2, 3 or 4 and

R and Y are as defined above.

The alkyl group substituents may be aliphatic (straight chain orbranched) or cyclic, and may be substituted with, for example, oxygen,nitrogen, sulphur and/or phosphorus.

A wide range of ligands for these complexes are envisaged, including:

a) Phosphines and arsines of the general formula Q₂ B(CD₂)_(n) BQ₂,where B is P or As; Q is H or aryl or substituted or unsubstitutedalkyl, preferably C1-C4 alkyl or phenyl; n is 1, 2, 3 or 4; and (CD₂) isa substituted or unsubstituted methylene group. Related compounds aredescribed in: U.S. Pat. No. 4,481,184, U.S. Pat. No. 4,387,087, U.S.Pat. No. 4,489,054, U.S. Pat. No. 4,374,821, U.S. Pat. No. 4,451,450,U.S. Pat. No. 4,526,776, EP-A-0266910 (Amersham International; methylenebridged diphosphine complexes) , EP-A-0311352 (Amersham International;phosphines containing ether groups), and ligands of general type

    R.sup.3.sub.m B--(CH.sub.2).sub.n --W--(CH.sub.2).sub.n --W--(CH.sub.2).sub.n --BR.sup.3.sub.m

where

B is P or As,

W is NR, S, Se, O, P or As,

R³ is H or hydrocarbon such as C1-C6 alkyl or aryl,

m is 1 or 2, and

n is 1, 2, 3 or 4.

b) Methylene Diphosphonate (MDP)

c) Thiourea (TU)

d) Thiomalate (TMA)

e) Dimercaptosuccinic acid (DMSA)

f) Gluconate (GLUC)

g) Ethane-1-hydroxy -1,1-diphosphonate (EHDP)

h) Diethylene triamine pentaacetic acid (DTPA)

i) N-(2,6-[Dialkyl]phenyl carbamoylmethyl) iminodiacetate

alkyl=Methyl (HIDA)

Ethyl (EHIDA)

^(i) Propyl (PIPIDA)

j) Dialkyl dithiocarbamate

k) Isonitriles of the general type C.tbd.NR⁴ R⁴ =alkyl, alkoxy, ether

l) BAT Derivatives--of the general type illustrated below, andspecifically:

i) R⁵ =R¹¹ =H R⁶,7,9,10 =Et R⁸ =N-methylspiropiperidinyl

ii) R⁵ =R¹¹ =H R⁶,7,9,10 =Et R⁸ =N-ethylspiropiperidinyl

iii) R⁵ =R¹¹ =H R⁶,7,9,10 =Et R⁸ =N-isopropylspiropiperidinyl ##STR3##m) phenanthroline, n) pentane-2,4-dione,

o) bipyridyl,

p) Other ligands having propylene amine oxime backbone of the generalstructural types described in EPA 123504 and 194843: ##STR4## q)Bisthiosemicarbazones of the formula: ##STR5## where the various groupsR¹² can be the same or different and are H and/or alkyl and/or arylsubstituents. Other suitable ligands are shown in Table 1.

The invention further provides methods for the preparation of theaforementioned complexes of technetium. One such method involves thederivatisation of technetium oxo-containing species by condensation withhydrazines or amines (equation A), isocyanates (equation B),sulphinylamines (equation C) or pnosphinimines (equation D):

    L.sub.n Tc═O+H.sub.2 NR→L.sub.n Tc═NR+H.sub.2 O A

    L.sub.n Tc═O+OCNR→L.sub.n Tc═NR+CO.sub.2    B

    L.sub.n Tc═O+OSNR→L.sub.n Tc═NR+SO.sub.2    C

    L.sub.n Tc═O+Ph.sub.3 P═NR→L.sub.n Tc═NR+Ph.sub.3 P═O                                                   D

wherein R, L and n are defined as above. The driving force for thesereactions is the formation of a stable product containing the former oxofunction (i.e. water, carbon dioxide, sulphur dioxide or phosphineoxide), which is generally easily removed after the oxo group transfer,leaving the desired technetium hydrazido (2-) or imido complex.

An alternative method of preparation involves the reaction of hydrazines(equation E) or amines (eisner aliphatic or aromatic) (equation F) withcomplexes containing technetium-halogen bonds:

    L.sub.n Tc Cl.sub.2 +H.sub.2 NNR.sup.1 R.sup.2 →L.sub.n Tc═NNR.sup.1 R.sup.2 +2HCl                            E

    L.sub.n Tc Cl.sub.2 +H.sub.2 NR→L.sub.n Tc═NR+2HCl F

where

L, R, R¹ and R² are as previously defined.

The driving force for these reactions is the concomitant formation o fthe volatile, easily removed hydrogen halide during the metathesisreaction.

It will be appreciated that the hydrazides and diazenides can beconsidered as essentially being functionalised imide ligands. Thehydrazide (2-) ligand, ═NNR¹ R², is just the imide ligand, ═NR, where Ris NR¹ R² ; and the diazenide ligand results when R₁ is hydrogen. Inthis case, the intermediate hydrazide (2-) complex is deprotonated by abase to give a metal-diazenide complex with concomitant reduction of themetal centre: ##STR6## In the reactions reported herein, the base isalways the added excess of hydrazine in the solution.

Turning now to the preparation of the technetium complexes containing animido moiety, the approach has been to replace the oxo function in[TcOX₄ ]⁻ (X═Cl, Br) using arylisocyanates (reaction type equation B).This formed a convenient entry point into the work by extending anestablished route for the synthesis of Tc═NR complexes. This method hasonly been previously used for generation of neutral imido products fromneutral transition metal oxo starting materials. The work reported hereis thus the first example of the method extended to the preparation ofanionic transition metal imido complexes, and also to technetiumchemistry.

Reaction of [Tc^(V) OX₄ ]⁻ with excess ArNCO in refluxing dry tolueneunder nitrogen gives excellent yields of the desired Tc^(V) -imidoproducts isolated as solids on ether trituration of the residue obtaineddirectly from the reaction mixture (equation G): ##STR7## X: Cl, 95-100%1 X═Br, 74% 2

Even though the method gives good yields of reasonably pure solids, thereaction is not trivial. The starting isocyanates are quite moisture andair sensitive such that the reaction must be strictly performed under anatmosphere of N₂. 1 and 2 are black-blue solids that are also quitesensitive to adventitious moisture, however, they are stable under dryN₂. That the products are very sensitive to moisture is evidenced by thefact that if reagent grade diethyl ether is used in the triturationphase of the workup procedure instead of anhydrous ether, then theproduct is isolated as a red-brown insoluble polymeric compound. Theproducts also do not always chromatograph (HPLC) satisfactorily.

The products [Tc(Ntol)X₄ ]⁻ contain the new core moiety [Tc^(V) ═NR]³⁺which is formally analogous to the known [Tc═O]³⁺ core . [Tc(NR)X₄ ]⁻ isa sixteen electron species in which the imido ligand functions as a fourelectron donor; the technetium-nitrogen bond is therefore expected to bea short, linear multiple [Tc═NR] bond. Attempted structuralcharacterisation of [Tc(Ntol)Cl₄ ]⁻ as its PPh₄ ⁺ salt by X-raycrystallography has so far been unsuccessful due to its sensitivenature. The products 1 and 2 are very good starting materials for thepreparation of many new Tc═NR complexes.

In view of the somewhat sensitive nature of 1 and 2, investigation ofmuch more stable Tc-imido complexes was undertaken. The directmetathesis reactions of [TcOCl₄ ]⁻ with aromatic amines was undertakenin the presence of phosphine ligands. Reactions of this type may showpromise in ^(99m) Tc chemistry in view of the wide variety ofsubstituted aromatic amines available commercially.

Reaction of [TcOCl₄ ]⁻ with ArNH₂ in refluxing MeOH in the presence ofthe monodentate phosphine PPh₃ gives the green-brown neutral Tc^(V)imido complexes which analyse for [Tc(NR)Cl₃ (PPh₃)₂ ] (equation H):##STR8##

Chromatographic analysis (HPLC, beta detection) of these products showonly one significant ⁹⁹ Tc-containing species. These neutral Tc^(V)complexes also contain the new [Tc^(V) ═NR]³⁺ core. They arediamagnetic, air-stable solids which are very soluble in CH₂ Cl₂, CHCl₃,moderately soluble in alcohols, and insoluble in ether and petrol. Theyexhibit a singlet (ca. 30 ppm) in the ³¹ P NMR spectrum, indicating twotrans-PPh₃ groups in identical environments. Structural characterisationof 3 by X-ray has now been carried out and FIG. 1 gives a Ball and Stickrepresentation of the complex molecule. The diagram shows a lineartolylimide group and the two PPh₃ groups to be trans. The [Tc═Ntol] unitin 3 may therefore be correctly assigned as a linear four electron donorimido ligand, and the complex is formally an 18-electron species.

This work therefore represents the first structurally characterisedTc^(V) -imido complex.

The [Tc(NR)Cl₃ (PPh₃)₂ ] compounds are much superior starting materialsthan [Tc(NR)X₄ ]⁻ because these are much more stable Tc═NR species.

Reaction of [TcOCl₄ ]⁻ with excess amine and dppe in refluxing MeOH orEtOH allows the isolation of good yields of the cationic Tc-imidocomplexes [Tc^(IV) (NC₆ H₄ Z)Cl-(dppe)₂ ]⁺ as their BPh₄ ⁻ salts(equation I): ##STR9##

These complexes 6,7, and 8 are all air-stable darkly coloured cationicTc^(IV) -imido complexes. Chromatographic analysis (HPLC, betadetection) indicates single ⁹⁹ Tc-containing species. They are quitesoluble in CH₂ Cl₂ and insoluble in ether, petrol and alcohols. They maybe conveniently recrystallised from CH₂ Cl₂ /MeOH.

Their assignment as Tc(IV) complexes is from the followingcharacterisation: The analysis stoichiometry fits the formula[Tc(NR)Cl(dppe)₂ ](BPh₄). Although γTc═N is not assignable there is noevidence for γNH in the infrared. The compounds exhibit very broadenedNMR spectra (¹ H, ³¹ P) at room temperature which are not easilyassigned. They are assumed to be paramagnetic Tc^(IV) imido complexesand not Tc^(III) -amido (TcNHR) complexes on this basis.

This represents another new core, the [Tc^(IV) ═NR]²⁺ moiety. Evidencefor the existence of this new Tc^(IV) core comes from the structuralcharacterisation of a [Tc^(IV) -hydrazido(2-)bis(dppe)Cl]⁺ cation whichcontains a [Tc^(IV) NNR₂ ]²⁺ core¹⁸. Hydrazido(2-) and imido(2-) areformally analogous. Further evidence comes from the existence andrelative stability of the analogous [Tc^(IV) ═O_(V) ]²⁺ core from theelectrochemical reduction of some Tc^(V) oxo Schiff base complexes.

It is to be understood that reactions of the aforementioned type A-F arewell known for the synthesis of various transition metal hydrazido (2-)and imido complexes³,10. While it is believed that they have notpreviously been used for the production of technetium complexes of thekind described and claimed herein, it is acknowledged that the synthesisof technetium-nitride complexes using hydrazine hydrochloride itself hasalready been reported¹⁵,16.

Using the approach of equation A above, the reactions of hydrazines with[NBu₄ ] [TcOCl₄ ] were studied, and the intermediate products furtherfunctionalised with mono- or bi-dentate ligands. In particular, thereaction of complexes containing technetium-oxo moieties [Tc═O] withmono-substituted hydrazines or 1,1-disubstituted hydrazines producestechnetium-diazenide or technetium-hydrazide (2-) species.

The facile synthesis of [TcCl(NNPh)₂ (PPh₃)₂ ] from [Bu₄ N][TcOCl₄ ],PhNHNH₂, and PPh₃ in methanol under reflux has been demonstrated.²⁵ Thiscomplex proved to be somewhat insoluble and could not be satisfactorilyrecrystallised due to its poor solubility. This unsubstitutedphenyl-diazenido-complex thus appears to be polymeric, possiblycontaining chloro-bridges. Consequently it was not thought to be asuitable starting material for investigation of substitution chemistry.

Use of 4-substituted hydrazine hydrochlorides 4-XC₆ H₄ NHNH₂.HCl (X═Cl,CH₃) has lead to the preparation of the analogous bisdiazenido-complexes[TcCl (NNC₆ H₄ X)₂ (PPh₃)₂ ] (X═Cl, 9; X═CH₃, 10). These air-stableorange crystalline solids are reasonably soluble compounds and are muchsuperior starting materials. Complex 9 (X═Cl) in particular has provedto be the most suitable for a systematic investigation of thesubstitution chemistry of the technetium bis diazenido-complexes, givingrelatively clean products on reaction with the appropriate ligand.

A most important development in this work is the fact that thesediazenido-complexes [TcCl(NNR)₂ (PPh₃)₂ ] may also be synthesiseddirectly from [TcO₄ ]⁻. Reaction of [NH₄ ] [TcO₄ ] with ClC₆ H₄NHNH₂.HCl and PPh₃ in dry methanol under reflux gives a good (60-70%)yield of [TcCl(NNC₆ H₄ Cl)₂ (PPh₃)₂ ] 9. Many variations in experimentalconditions were tried. The best method is reported here. This resultsuggests that all technetium diazenido-complexes may be synthesised ingood yield directly from [TcO₄ ]⁻.

In order to investigate which complexes could be synthesised directlyfrom [TcO.sub. 4]⁻ in future work, it has been important to demonstratethat the diazenido- (and imido-) cores may be incorporated into a widevariety of complex types. For diazenido-cores this has mainly beenapproached by the systematic substitution of 9.

Reaction of 9 with excess dppe in methanol under reflux gives pure[TcCl(NNC₆ H₄ Cl)(dppe)₂ ]⁺, 12 isolated as orange crystalline BPh₄ ⁻ orPF₆ ⁻ salts in good yield. Complexes of this type may also be prepareddirectly from [NH₄ ][TcO₄ ].

Reaction of 9 with dmpe under similar conditions leads to the isolationof a pale-pink cationic solid (HPLC retention time 10 minutes, singlespecies) containing no nitrogen. This product could not be isolated inpure form, but is tentatively formulated as [Tc^(I) (dmpe)₃ ][BPh₄ ].The analogous reaction under less forcing conditions at room temperatureleads to the desired cation [TcCl(NNC₆ H₄ Cl)(dmpe)₂ ]⁺ isolated as itsPF₆ ⁻ salt (HPLC retention time 9.6 minutes, single species).

In order to elucidate the validity of both [Tc(N₂ Ar)₂ ]⁺ and [Tc(N₂Ar)]²⁺ as new cores for the development of Tc-based radiopharmaceuticalproducts it was necessary to investigate the lability of the --N₂ Arunit on reaction with other ligands. Detailed HPLC experiments (betadetection) were performed to see if a bis diazenido-intermediate wasformed in the preparation of the cation 12 (retention time 14 minutes)from the starting material 9 (retention time 9.4 minutes). The HPLCresults showed that the cation formed after only 15 minutes stirring atroom temperature, and that no other Tc-containing intermediate wasdetected. This proves that one --N₂ Ar moiety is very labile, and iseasily lost in solution at room temperature in the presence of theappropriate ligand to give the monodiazenido-product.

Reaction of 9 and 10 with the less bulky phosphines (PMe₂ Ph, PMePh₂)gave single species in solution (HPLC). However, the high solubilityprecluded further workup of these apparently cationic products. Reactionof [Bu₄ N] [TcOCl₄ ], XC₆ H₄ NHNH₂.HCl (X═Cl, CH₃) and the appropriatephosphine also leads to isolation of these solutions (HPLC).

Reaction of the commercially available hydrazine O₂ NC₆ H₄ NHNH₂ with[Bu₄ N] [TcOCl₄ ] and PPh₃ in methanol leads to the isolation of thelime-green Tc(III) monodiazenido-complex [TcCl₂ (NNC₆ H₄ NO₂)(PPh₃)₂ ],11 in reasonable yield. Apparently a bis diazenido-complex is not formedfrom reaction of this nitro-substituted phenyl hydrazine. The complex 11promises to be a useful starting material for the preparation of avariety of monodiazenido-complexes as it has two easily replaceablechlorides. In the presence of dppe in methanol-toluene under refluxcomplex 11 gives orange [TcCl(NNC₆ H₄ NO₂)(dppe)₂ ]⁺, 13 isolated as itsBPh₄ ⁻ salt in good yield. [TcCl(NNC₆ H₄ NO₂)(dmpe)₂ ][PF₆ ] (retentiontime 10 minutes, single species) was prepared in high yield directlyfrom [TcOCl₄ ]⁻, the hydrazine, and dmpe in refluxing methanol-toluene.

Reaction of 9 with sodium dimethyldithiocarbamate in absolute ethanolunder reflux gives the novel orange Tc(III) diazenido-complex [Tc(NNC₆H₄ Cl) (S₂ CNMe₂)₂ (PPh₃)], 14 in reasonable (66%) yield. Complex 14 isair-stable both in the solid state and in solution. Recrystallisationfrom CH₂ Cl₂ /Et₂ O gives X-ray quality orange crystals. Satisfactoryelemental analysis and spectroscopic data suggest the formulation to becorrect. The room temperature ¹ H NMR spectrum of 14 is indicative ofits coordination geometry. The four methyl groups in 14 appear as foursharp singlets. This resonance pattern shows that the twodithiocarbamato ligands are non-equivalent, and is consistent with acis-conformation. This has to be confirmed by X-ray structure analysis.If the dithiocarbamato ligands were trans- and the four methyl groupsthus equivalent, the ¹ H spectrum would show a single resonance whichwould not be expected to change with temperature.

Reaction of 9 with maltol gives a dark-orange crystalline compound. Thisis a single species (HPLC) and analyses as [TcCl(NNC₆ H₄ Cl)(maltol)(PPh₃)₂ ], 15. This novel Tc(III) diazenido complex is formallyanalogous to the structurally characterised[ReCl(NNCOPh)(maltol)(PPh)₃)₂ ]²⁶, and is the first reported Tc complexcontaining the maltol ligand.

Reaction of 9 with the tetradentate N₂ O₂ (2-) ligand salenH₂ inmethanol-toluene under reflux in the presence of Et₃ N gives the neutraldark-green Tc(III) diazenido-complex [Tc(NNC₆ H₄ Cl) (salen) (PPh₃)], 16in good yield. Similar reaction of 9 with the obligately planartetradentate N₂ O₂ (2-) ligand salphenH₂ gave no well defined productsuggesting that a cis-geometry of the --N₂ Ar and PPh₃ groups ispreferred. Further evidence for a preferred cis-geometry is suggestedfrom the spectroscopic results of 14. This is expected to be confirmedby X-ray structure analysis.

Reaction of 9 with the N₂ S₂ ligand (HSCH(Me)CONHCH₂ --)₂ in thepresence of Et₃ N gave a dark-brown solid. The product was too insolublefor satisfactory analysis by NMR, but appeared to be diamagnetic.Elemental analysis on the product isolated directly from the reactionmixture suggested the formulation as a his diazenido-complex [Tc(NNC₆ H₄Cl)₂₋ (SCH(Me)CONHCH₂ CH₂ NHCOCH(Me)S)]_(x), 17.

Much effort has been directed to the development of a synthetic route toTc imido-complexes directly from [TcO₄ ]⁻. Reaction of aqueousmethanolic solutions of [TcO₄ ]⁻ with aromatic amine and PPh₃ in thepresence of concentrated HCl gives only low yields of the desired Tc(V)imido-complexes [TcCl₃ (NAr)(PPh₃)₂ ]. These complexes have beenprepared previously from [Bu₄ N][TcOCl₄ ].²⁵ The nature of the reactionfrom [TcO₄ ]⁻ appears to be very dependent on the concentration of HClused. Use of excess HCl gives [TcCl₄ (PPh₃)₂ ].

The use of amine hydrochloride (ArNH₃ Cl) as an alternative to theaddition of HCl in this reaction has also been investigated in somedetail. [TcO₄ ]⁻ reacts with ArNH₃ Cl and PPh₃ in aqueous methanol togive a bright blue, neutral product in high yield after about 20 minutesstirring at room temperature. This product appears to be independent ofthe aromatic amine hydrochloride used. The blue compound appears to bediamagnetic (NMR) and shows evidence for coordinated PPh₃, but containsno nitrogen. This compound analyses reasonably as [Tc₂ Cl₄ (PPh₃)₄ ]which is analogous to many known Re--Re multiply bonded species. Use ofaliphatic amine hydrochlorides (RNH₃ Cl) leads to rapid conversion toblack insoluble "TcO₂.xH₂ O".

Reaction of [NH₄ ][TcO₄ ] with the hydrochloride of anthranilic acid(2-HO₂ CC₆ H₄ NH₃ Cl) under analogous conditions gives a lime-greenprecipitate. This analyses reasonably well as [TcCl₂ (NC₆ H₄ CO₂)(PPh₃)₂], 18 and is expected to have the novel structure containing a bent TcNCframework. The bent chelating imidobenzoate (3-) ligand is thus a newcore moiety for technetium. The complex 18 may also be prepared from[TcOCl₄ ]⁻ in lower yield. Anthranilic acid is known to react with[ReOCl₃ (PPh₃)₂ ] in ethanol to give the chelating imidobenzoate (3-)complex [ReCl(OEt) (NC₆ H₄ CO₂)(PPh₃)₂ ].²⁷ ##STR10##

This is a major development as it suggests that imido-complexes are moregenerally accessible from [TcO₄ ]⁻. The chelate effect must in some waystabilise the formation of this imido-ligand. The establishment of aconjugation pathway through the M═N, C═C, and C═O may be a driving forcefor its formation. The reaction of [TcO₄ ]⁻ and anthranilic acidhydrochoride in the presence of a wide variety of non-phosphine ligandsis envisaged.

Much effort has been directed to synthesis of Tc imido-ligands from[TcO₄ ]⁻ using the hydrazines RCONHNHAr (R═CH₃, Ph), and also theirhydrochlorides as a source of the NAr ligand. Use of the symmetricallysubstituted hydrazines RNHHNR (R═Me, Et, PhCO, Ph) is also envisaged.Preliminary experiments for both [TcO₄ ]⁻ and [TcOCl₄ ]⁻ have shown thatmixtures of products are being formed (HPLC).

Our work has resulted in the synthesis of two new classes of technetiumcomplexes with hydrazido (2-), i.e. .sup.═ NNR₂, and diazenido i.e.--NNR substituents, at both the carrier added (⁹⁹ Tc) and the no carrieradded (^(99m) Tc) levels. Both neutral and cationic derivatives havebeen prepared within each class. These complexes are useful asradiopharmaceuticals and thus provide a new range of such reagents.

Specifically, the following new complexes containing hydrazido (2-) anddiazenido moieties have been prepared:

⁹⁹ Tc: Carrier Added Level

[Tc^(V) (NNMePh)Cl₃ (PPh₃)₂ ]

[Tc^(V) (NNMePh)Cl₂ (PMe₂ Ph)₃ ][PF₆ ]

[Tc^(V) (NNMePh)Cl(Et₂ NCS₂)₂ ]

[Tc(N₂)Cl(dppe)₂ ]

[Tc^(IV) (NNMe₂)Cl(dppe)₂ ][PF₆ ]

[Tc^(V) O(NH)dppe][PF₆ ]

[Tc^(III) (NNPh)₂ Cl(PPh₃)₂ ]

[Tc^(III) (NNPh)Cl(dppe)₂ ][PF₆ ]

[Tc(NNC₆ H₄ Cl)Cl(dppe)₂)[PF₆ ]

[Bu₄ N][Tc(NC₆ H₄ CH₃)Br₄ ], [Bu₄ N][Tc(NC₆ H₄ CH₃)Cl₄ ], Tc(NC₆ H₄Z)Cl₃ (PPh₃)₂ where Z═CH₃, Br, Cl, [Tc(NC₆ H₄ Z)Cl(dppe)₂ ][BPh₄ ],where Z is as above.

^(99m) Tc: No-Carrier Added Level*

[Tc^(III) (NNPh)Cl(L)₂ ]⁺

L=dmpe, dppe, P46, P53, P56, P68, PL28, PL31, PL34, PL37, PL38, PL40,PL42, PL43, PL46, PL49, PL50.

[Tc^(III) (NNC₆ H₄ NO₂)Cl(L)₂ ]⁺

L=dmpe

[Tc^(IV) (NNMePh)Cl(L)₂ ]⁺

L=dmpe, P34, P46, P53, P65, P68, PL28, PL38

*The structures of the ligands, L, given here are shown in Table 1.

Of these, animal biodistribution data has been obtained for thefollowing ^(99m) Tc species and the results are shown in Tables 2, 3 and4:

    [Tc.sup.III (NNPh)Cl(L).sub.2 ].sup.+ L=dmpe, PL28, P46, PL42, PL43, P65, PL50. PL38                                                (Table 2)

    [Tc.sup.III (NNC.sub.6 H.sub.4 NO.sub.2)Cl(L).sub.2 ].sup.+ L=dmpe (Table 3)

    Tc.sup.IV (NNMePh)Cl(L).sub.2 ].sup.+ L=dmpe, P46, P65     (Table 4)

This invention will now be further illustrated by the followingExamples:

⁹⁹ Tc Complexes

All reactions were performed under an atmosphere of nitrogen usingpredried, distilled solvents unless noted otherwise. [NBu₄ ] [TcOCl] wasprepared by the literature procedure²⁰. All other reagents used wereobtained from commercial sources and used as received. Aqueous solutionsof [NH₄ ][TcO₄ ] were obtained from Amersham International plc.

All complexes were characterised by elemental analysis, IR, ¹ H NMR and³¹ P NMR. Only analytical data are included here but spectroscopicinformation is available. In addition to the above physicalcharacterisation of the complexes single crystal X-ray structures havebeen obtained for four complexes: [Tc(NNPh)Cl(dppe)₂ ][PF₆ ],[Tc(NH)O(dppe)₂ ][PF₆ ], [Tc(NNMe₂)Cl(dppe)₂ ][PF₆ ] and Tc(NC₆ H₄CH₃)Cl₃ (PPh₃)₂.

EXAMPLE 1 Reaction of (Bu₄ N)[TcOX₄ ] (X═Cl, Br) with 4-Tolylisocyanate

i) Tetrabutylammonium(1+)tetrachloro(p-tolylimido) technetate (V) (1-),(Bu₄ N) [Tc(Ntol)Cl₄ ]1

(Bu₄ N)[TcOCl₄ ] (0.194 g, 0.39 mmol) was suspended in dry degassedtoluene (10 ml) and MePhNCO (0.25 ml, 1.98 mmol, 5 equivalents) wasadded. The mixture was then vigorously refluxed under N₂ for 45 minutes.After cooling to room temperature the toluene was decanted off, and theblack residue was triturated with dry diethyl ether (10 ml) beforecollection of the blue-black solid 1 by filtration. On washingthoroughly with diethyl ether the product was dried in vacuo. (Yield0.229 g, 0.39 mmol, 100%). In similar preparations of 1 the yield wasnever less than 95% and therefore the conversion was considered to beessentially quantitative. (Found: C, 49.31; H, 7.22; N, 5.02. calc forTcC₂₃ H₄₃ N₂ Cl₄ : C, 47.03; H, 7.37; N, 4.77% ); ¹ H NMR (d₆ -DMSO)0.9[12H, broad unresolved triplet, (CH₃ (CH₂)₃)₄ N]; 1.4[24H, broadmultiplet, (CH₃ (CH₂)₃)₄ N]; 2.2[3H, singlet, CH₃ C₆ H₄ N--Tc];7.0-7.4[4H, multiplet, CH₃ C₆ H₄ NTc]; v_(max). (Nujol mull, KBr plates)1170 m br cm⁻¹ (Tc═N, tentative assignment).

ii) Tetrabutylammonium(1+)tetrabromo(p-tolylimido) technetate (V) (1-),(Bu₄ N)[Tc(Ntol)Br₄ ] 2

The blue-black product 2 was prepared in a similar fashion to 1 using(Bu₄ N) [TcOBr₄ ] (0.268 g, 0.396 mmol) and MePhNCO (0.25 ml, 1.98 mmol,5 equivalents) in refluxing dry toluene (15 ml). (Yield 0.224 g, 0.29mmol, 74%). HPLC retention time 9.6 minutes, single species; (Found : C,36.73; H, 6.43; N, 3.16. calc for TcC₂₃ H₄₃ N₂ Br₄ : C, 36.10; H 5.66; N3.66%); ¹ H NMR (CDCl₃) 1.0[12H, broad unresolved triplet, (CH₃ (CH₂)₃)₄N]; 1.5[24H, broad multiplet, (CH₃ (CH₂)₃)₄ N]; 2.27[3H, singlet, CH₃ C₆H₄ NTc]; 6.9-7.5[4H, multiplet, CH₃ C₆ H₄ NTc]; v_(max). (Nujol mull,KBr plates) 1175 cm⁻¹ (Tc═N, tentative assignment).

EXAMPLE 2 Reactions of (Bu₄ N)[TcOCl₄ ] with Aromatic Amines (4-ZC₆ H₄NH₂, Z═CH₃, Br, Cl) in the Presence of Triphenylphosphine, PPh₃

i) Trichloro(p-tolylimido)bis(triphenylphosphine) technetium (V), Tc(NC₆H₄ Z)Cl₃ (PPh₃)₂ Z═CH₃, 3

(Bu₄ N) [TcOCl₄ ] (0.216 g, 0.43 mmol), CH₃ C₆ H₄ NH₂ (0.07 g, 0.65mmol, 1.5 equivalents) and PPh₃ (0.34 g, 1.3 mmol, 3 equivalents) wererefluxed in dry methanol (10 ml) under N₂ for 40 minutes. After coolingto room temperature, the brown-green mixture was evaporated to 5 ml, anddiethyl ether (15 ml) was added to aid precipitation of 3. Thegreen-brown product was collected by filtration, washed thoroughly withether and dried. The product could be recrystallised from CH₂ Cl₂/hexane mixture. (Yield 0.094 g, 0.11 mmol, 26%). HPLC retention time10.8 minutes, single species; (Found: C, 59.01; H, 4.35; N, 1.76; Cl,12.80. calc for TcC₄₃ H₃₇ NCl₃ P₂ : C, 61.84; H, 4.46; N, 1.68; Cl,12.74%); ¹ H NMR (CDCl₃) 2.2[3H, s, CH₃ C₆ H₄ NTc]; 6.5-6.8[4H, m, CH₃C₆ H₄ NTc]; 7.0-8.0[3.0H, m, phenyl H]. There was no evidence of NH inthe proton spectrum; ³¹ P-{¹ H} NMR (CDCl₃) 30.02 s ppm; v_(max). (Nujolmull, KBr plates) 1165 cm⁻ (Tc═N, tentative assignment). There were noabsorptions which could be attributed to ^(v) NH.

ii) Trichloro(p-bromophenylimido)bis(triphenylphosphine) technetium (V),Tc(NC₆ H₄ Z)Cl₃ (PPh₃)₂ Z═Br, 4

(Bu₄ N) [TcOCl₄ ] (0.210 g, 0.42 mmol), BrC₆ H₄ NH₂ (0.11 g, 0.64 mmol,1.5 equivalents) and PPh₃ (0.331 g, 1.26 mmol, 3 equivalents) wererefluxed in dry methanol (10 ml) to give on workup and recrystallisationfrom CH₂ Cl₂ /hexane a very low yield of brown solid 4. (Yield 0.052 g,0.06 mmol, 14%). HPLC retention time 9.6 minutes, single species;(Found: C, 54.38; H, 4.00; N, 1.53; Cl, 10.56. calc for TcC₄₂ H₃₄ NP₂Cl₃ Br: C, 56.05; H, 3.81; H, 1.56; Cl, 11.82. calc for TcC₄₂ H₃₄ NP₂Cl₃ Br.1/2 CH₂ Cl₂ : C, 54.45; H, 3.72; N, 1.48; Cl, 14.95%); ¹ H NMR(CDCl₃) 5.25[s, CH₂ Cl₂ ]; 6.8[4H, m, BrC₆ H₄ NTc]; 7.0-8.0[30H, m,phenyl H]; ³¹ P-{¹ H} NMR (CDCl₃) 29.93 s ppm; v_(max). (Nujol mull, KBrplates) 1165 cm⁻¹ (Tc═N, tentative assignment).

iii) Trichloro(p-chlorophenylimido)bis(triphenylphosphine) technetium(V), Tc(NC₆ H₄ Z)Cl₃ (PPh₃)₂ Z═Cl, 5

(Bu₄ N)[TcOCl₄ ] (0.272 g, 0.545 mmol), ClC₆ H₄ NH₂ (0.104 g, 0.82 mmol,1.5 equivalents) and PPh₃ (0.43 g, 1.64 mmol, 3 equivalents) wererefluxed In dry methanol (10 ml) to give a very low yield of brown solid5. (Yield 0.084 g, 0.098 mmol, 18%). HPLC retention time 9.2 minutes,single species; (:Found: C, 55.85; H, 3.86; N, 1.63. calc for TcC₄₂ H₃₄NP₂ Cl₄ : C, 58.96; H, 4.00; N, 1.64%); ¹ H NMR (CDCl₃) 6.5-6.7[4H m,ClC₆ H₄ NTc]; 7.0-8.0[30H, m, phenyl H]; ³¹ P-{¹ H} NMR (CDCl₃) 29.87 sppm; v_(max). (Nujol mull, KBr plates ) 1170 cm⁻¹ (Tc═N, tentativeassignment.

EXAMPLE 3 Reactions of (Bu₄ N)[TcOCl₄ ] with Aromatic Amines (4-ZC₆ H₄NH₂, Z═CH₃, Br, Cl) in the Presence of Bis(diphenylphosphino)ethane,dppe

i) [Tc(NC₆ H₄ Z)Cl(dppe)₂ ](BPh₄) Z═CH₃, 6

(Bu₄ N) [TcOCl₄ ] (0.333 g, 0.67 mmol), CH₃ C₆ H₄ NH₂ (0.36 g, 3.33mmol, 5 equivalents), and dppe (0.80 g, 2.0 mmol, 3 equivalents) in drydegassed methanol (20 ml) were refluxed for 1 hour. After cooling toroom temperature, the violet mixture was filtered in to a clean flask toremove some insoluble red material. Sodium tetraphenylborate (0.23 g,0.67 mmol) in methanol (5 ml) was added with stirring to immediatelyprecipitate out a copious amount of violet solid 6. The product wascollected by filtration and washed thoroughly with MeOH, and then ether.The product could be recrystallised from CH₂ Cl₂ /MeOH or CH₂ Cl₂/hexane. (Yield 0.544 g, 0.40 mmol, 60%). HPLC retention time 8.4minutes, one major species; (Found: C, 74.09; H , 7.09; N, 1.70; Cl,3.22. calc for TcC₈₃ H₇₅ NClP₄ B: C, 73.54; H, 5.58; N, 1.03; Cl,2.62%).

There are no infrared absorptions assignable to NH stretches, and the^(v) Tc═N stretch could not be assigned unambiguously. The product gavea broadened ¹ H NMR spectrum and was assumed to be paramagnetic Tc(IV).The ³¹ P NMR spectrum also showed broadened resonances.

If less ArNH₂ was used in the reaction a red precipitate believed to be[Tc^(III) Cl₂ (dppe)₂ ]Cl forms in approximately 50% yield from the MeOHon cooling to room temperature.

ii) [Tc(NC₆ H₄ Z)Cl(dppe)₂ ](BPh₄) Z═Br, 7

(Bu₄ N)[TcOCl₄ ] (0.179 g, 0.36 mmol), BrC₆ H₄ NH₂ (0.31 g, 1.79 mmol, 5equivalents) and dppe (0.429 g, 1.08 mmol, 3 equivalents) were refluxedin dry methanol (10 ml, 1 hour). NaBPh₄ (0.122 g, 0.36 mmol) in MeOH (5ml) was added to the cooled filtered reaction mixture with stirring toisolate 7 as a maroon solid on filtration. (Yield 0.325 g, 0.23 mmol,64%). HPLC retention time 7.6 minutes, one major species. Analysis onthe crude material gave (Found: C, 73.19; H, 5.91; N, 0.89; Cl, 3.19.calc for TcC₈₂ H₇₂ NBrClP₄ B: C, 69.33; H, 5.11; N, 0.99; Cl, 2.50%) andsuggests contamination with BPh₄ ⁻ or Cl⁻. The product could berecrystallised from CH₂ Cl₂ /MeOH.

iii) [Tc(NC₆ H₄ Z)Cl(dppe)₂ ](BPh₄) Z═Cl, 8

(Bu₄ N)[TcOCl₄ ] (0.28 g, 0.56 mmol), ClC₆ H₄ NH₂ (0.358 g, 2.8 mmol, 5equivalents) and dppe (0.67 g, 1.68 mmol, 3 equivalents) were refluxedin dry methanol (15 ml, 75 minutes). NaBPh₄ (0.19 g, 0.56 mmol) in MeOH(5 ml) was added to the cooled filtered reaction mixture with stirringto precipitate out the dark maroon solid 8 which was collected byfiltration. (Yield 0.497 g, 0.36 mmol, 64%). HPLC retention time 8.0minutes, one major species. Analysis on the crude material gave (Found:C, 73.56; H, 5.94; N, 1.72; Cl, 3.26. calc for TcC₈₂ H₇₂ NCl₂ P₄ B: C,71.57; H, 5.27; N, 1.02; Cl, 5.15%) and suggests contamination with BPh₄⁻. The product could be recrystallised from CH₂ Cl₂ /MeOH.

EXAMPLE 4 The preparation of [Tc(NNPh)₂ Cl(PPh₃)₂ ]

Dry, distilled MeOH (5 cm³) was added to a reaction flask containing amagnetic stirring bar, 222 mg PPh₃ (0.85 mmol) and 70 mg [NBu₄ ][TcOCl₄] (0.14 mmol). This gave an orange suspension containing undissolvedPPh₃. After five minutes 0.60 cm³ of PhNHNH₂ (6.1 mmol) was added andthe reaction mixture was heated to reflux for one hour. The solution wascooled to room temperature overnight and the resultant yellow-goldprecipitate was collected, washed with MeOH (5 cm³) and EtO₂ O (10 cm³).The yield of Tc(NNPh)₂ Cl(PPh₃)₂, after drying in vacuo, was 94 mg (0.11mmol, 80%) based on technetium. This material is only partially solublein halogenated solvents and insoluble in alcohols. Hence, attempts topurify the complex were only partially successful. Analysis calculatedfor C₄₈ H₄₀ ClN₄ P₂ Tc: 66.32% C; 4.64% H; 6.45% N. Found: 64.23% C;4.28% H; 4.87% N.

EXAMPLE 5 The preparation of [Tc(NNPh)Cl(dppe)₂ ][PF₆ ]

Method 1

52 μl of PhNHNH₂ (0.53 mmol) was added to a stirred solution of 80 mg[NBu₄ ][TcOCl₄ ] (0.16 mmol) in 5 cm³ MeOH. After five minutes 253 mg ofdppe (0.64 mmol) was added as a solid to the stirred reaction mixtureand this was then heated to reflux for one hour. The solution was cooledto room temperature, filtered, and an excess of NH₄ PF₆ (1 g) in 3 cm³water was added to precipitate an orange compound. This was collected,washed with MeOH (15 cm³) and Et₂ O (30 cm³), and dried in the air. Thisgave 95 mg of product (0.08 mmol, 50%). The complex could berecrystallised from CH₂ Cl₂ /EtOH. Analysis calculated for C₅₈ H₅₃ ClF₆N₂ P₅ Tc: 58.97% C; 4.61% H; 2.37% N. Found: 58.92% C; 4.68% H; 2.70% N.

Method 2

A methanolic solution of [NH₄ ][TcO₄ ] was prepared by adding 0.50 cm³of a 0.29M aqueous solution of [NH₄ ][TcO₄ ] (0.15 mmol) to 3.0 cm³ ofreagent grade MeOH. Phenyl hydrazine (50 μl, 0.51 mmol) was then addedto this stirred solution. No reaction appeared to take place until 0.1cm³ of concentrated HCl was added to the reaction mixture five minuteslater. This was immediately followed by the addition of 241 mg dppe(0.81 mmol) as a solid. The reaction mixture was heated to reflux forone hour, cooled to room temperature and filtered to remove excess,unreacted dppe. An excess of [NH₄ ][PF₆ ] was added to the stirredsolution as a solid and the resultant suspension was stirred at roomtemperature overnight. The orange precipitate was then collected, washedwith ^(i) PrOH and Et₂ O and dried in vacuo to give 108 mg of[Tc(NNPh)(dppe)₂ Cl][PF₆ ] (0.09 mmol, 60%). The product was identifiedby comparison of its IR and ¹ H NMR spectra with those obtained from anauthentic sample prepared by Method 1.

EXAMPLE 6 The Preparation of [Tc(NNC₆ H₄ Cl)(dppe)₂ Cl][PF₆ ]

This complex was prepared according to Method 2 above from [NH₄ ][TcO₄ ](0.19 mmol), 129 mg trans-ClC₆ H₄ NHNH₂.HCl (1.07 mmol), 0.1 cm³concentrated HCl, and 561 mg dppe (1.41 mmol). Yield of [Tc(NNC₆ H₄Cl)(dppe)Cl][PF₆ ]: 298 mg, 0.24 mmol 84%. Analysis calculated for C₅₈H₅₂ Cl₂ F₆ N₂ P₅ Tc. 1/2 CH₂ Cl₂ : 55.99% C; 4.25% H; 2.23% N. Found:55.73% C; 4.37% H; 1.93% N.

EXAMPLE 7 The reaction of [NBu₄ ][TcOCl₄ ] with Benzoylhydrazine andPPh₃

This reaction was performed according to the Method 1 above for thesynthesis of Tc(NNPh)₂ Cl(PPh₃)₂ using 77 mg [NBu₄ ][TcOCl₄ ], 70 mgPhC[O]NHNH₂ (0.51 mmol) and 135 mg PPh₃ (0.51 mmol). After the reactionsolution had been heated to reflux for one hour and cooled to roomtemperature, a light orange compound precipitated and was collected,washed with MeOH (15 cm³) and Et₂ O (30 cm³) and then dried in the air.The compound was identified as TcNCl₂ (PPh₃)₂ by comparison of its IRand NMR spectroscopic characteristics with those of an authenticsample.⁸ The yield was 97 mg (0.14 mmol, 88%). Analysis calculated forC₃₆ H₃₀ Cl₂ NP₂ Tc: 61.12% C; 4.27% H; 1.98% N. Found: 60.66% C; 4.35%H; 2.32% N.

EXAMPLE 8 The reaction between [NBu₄ ][TcOCl₄ ], Benzoylhydrazine anddppe

This reaction was performed according to Method 1 above using 119 mg[NBu₄ ][TcOCl₄ ] (0.24 mmol), 91 mg PhC[O]NHNH₂ (0.67 mmol), and 323 mgdppe (0.81 mmol). The cooled reaction solution was filtered and anexcess of [NH₄ ][PF₆ ] was added with stirring. The orange complex wasidentified as [TcN(dppe)₂ Cl][PF₆ ] by comparison of its spectroscopicproperties with those of an authentic sample.²¹ Yield: 196 mg (0.18mmol, 75%). Analysis calculated for C₅₂ H₄₈ ClF₆ NP₅ Tc: 57.28% C; 4.44%H; 1.28% N. Found: 56.72% C; 4.84% H; 0.87% N.

EXAMPLE 9 The reaction between [NBu₄ ][TcOCl₄ ], H₂ NNH₂ and dppe

This reaction was performed by Method 1 above using 124 mg [NBu₄][TcOCl₄ ] (0.25 mmol), 15 μl H₂ NNH₂ (Aldrich, Anhydrous, 0.47 mmol)and 421 mg dppe (1.06 mmol). The reaction solution was heated to refluxfor 30 minutes, cooled to room temperature, filtered and an excess of[NH₄ ][PF₆ ] was added to the filtrate with stirring. The resultantorange-brown compound was collected by filtration. Yield: 144 mg (0.20mmol, 80%). This product was identified as the complex [TcN(dppe)₂Cl][PF₆ ].

EXAMPLE 10 The Synthesis of TcNNPhMe(PPh₃)₂ Cl₃

108 mg [NBu₄ ][TcOCl₄ ] (0.22 mmol) was dissolved in 10 cm³ dry MeOH and52 μl MePhNNH₂ (0.44 mmol) was added to the stirred solution. Thesolution changed from pale green to red-orange immediately. 211 mg PPh₃(0.80 mmol) was added to the reaction solution and the resultingsuspension was heated to reflux for one hour. The resulting suspensionwas cooled to room temperature and a large amount of a tan precipitatewas collected, washed with MeOH (15 cm³) and Et₂ O (30 cm³), and thendried in vacuo. The yield was 108 mg of a complex identified as[Tc(NNPhMe)Cl₃ (PPh₃)₂ ] (0.13 mmol 59%). Analysis calculated for C₄₃H₃₈ Cl₃ N₂ P₂ Tc: 60.82% C; 4.51% H; 3.30% N; 12.53% Cl. Found: 60.01%C; 4.17% H; 3.53% N; 12.20% Cl.

EXAMPLE 11 The Preparation of [Tc(NNPhMe)Cl₂ (PMe₂ Ph)₃ ][PF₆ ]

A red-orange solution was prepared by adding 0.10 cm³ MePhNNH₂ (0.85mmol) to a stirred solution of 1.47 mg [NBu₄ ][TcOCl₄ ] (0.30 mmol) in4.0 cm³ of MeOH. 0.20 cm³ of PMe₂ Ph was then added to the reactionmixture and this was then heated to reflux for 45 minutes to give aclear orange solution. The solution was then concentrated toapproximately 2 cm³ and then 94 mg [NH₄ ][PF₆ ] was added as a solid tothe stirred reaction mixture. The precipitate which formed was collectedand washed with 7:1 (v/v) Et₂ O-^(i) PrOH. The filtrate wasreconcentrated to give a second crop of gold-brown microcrystallinematerial. The yield was 138 mg of [Tc(NNMePh)Cl₂ (PMe₂ Ph)₃ ][PF₆ ](0.16 mmol, 54%). Analysis calculated for C₃₁ H₄₀ Cl₂ F₆ N₂ P₄ Tc:43.93% C; 4.76% H; 3.31% N. Found: 44.53% C; 5.22% H; 3.10% N.

EXAMPLE 12 The Preparation of [Tc^(V) (NNPhMe)Cl(Et₂ NCS₂)₂ ]

A red-orange solution was prepared as described above from 138 mg [NBu₄][TcOCl₄ ] (0.28 mmol) and 80 μl MePhNNH₂ (0.68 mmol) in 3 cm³ of MeOH.After this solution had been stirred at room temperature for fiveminutes, a solution of 200 mg NaS₂ cNEt₂.3H₂ O (0.89 mmol) in 2 cm³MeOH. The resulting dark red solution was heated to reflux for 30minutes, cooled to room temperature and the solvent was removed in vacuoto give a red, oily residue. This residue was taken up in 5 cm³ of ^(i)PrOH and this suspension was filtered to give 73 mg of a pale brownpowder which was washed with Et₂ O. The filtrate was concentrated toabout 1-2 cm³ volume and 50 cm³ Et₂ O was added. The precipitated thusformed was collected and identical to the original material isolated.The overall yield of the complex, identified as [Tc(NNMeph)Cl(Et₂ NCS₂)₂] was 111 mg (0.02 mmol, 71%). The complex could be recrystallised fromCH₂ Cl₂ /Et₂ O. Analysis calculated for C₁₇ H₂₇ ClN₄ S₄ Tc: 37.12% C;4.95% H; 10.19% N; 6.44% Cl. Found: 38% C; 5% H; 11% N; 9.4% Cl.

EXAMPLE 13 The Reaction between [NBu₄ ][TcOCl₄ ], MePhNNH₂ and dppe

An orange solution was prepared as described above from 100 mg [NBu₄][TcOCl₄ ] (0.20 mmol), 45 μl MePhNNH₂ (0.38 mmol) in 4 cm³ MeOH. 550 mgdppe (1.38 mmol) was then added to this stirred solution as a solid andthe resultant suspension was heated to reflux for one hour, cooled toroom temperature and filtered to remove unreacted dppe. An excess of[NH₄ ][PF₆ ] was added as a solid to the filtered solution to give a tanprecipitate which was washed with MeOH (20 cm³) and Et₂ O (10 cm³). Thisyielded 121 mg of [Tc(NH)O(dppe)₂ ][PF₆ ] (0.11 mmol, 55%). Analysiscalculated for C₅₂ H₄₉ F₆ NOP₅ Tc: 58.27% C; 4.61% H; 1.31% N. Found:56.90% C; 4.70% H; 1.61% N.

EXAMPLE 14 The Reaction of [NBu₄ ][TcOCl₄ ], Me₂ NNH₂ and dppe

Method 1

An orange-red solution was prepared as described above from 211 mg [NBu₄][TcOCl₄ ] (0.42 mmol), 35 μl Me₂ NNH₂ (0.46 mmol) in 5 cm³ MeOH andthen 366 mg dppe (1.40 mmol) was added as a solid. The reaction mixturewas heated to reflux for one hour, cooled to room temperature and ayellow precipitate was collected (72 mg of [Tc(N₂)(dppe)₂ Cl] (0.07mmol, 17%). An excess of [NH₄ ][PF₆ ] was added as a solid to thefiltrate to give a gold-brown precipitate (137 mg) of[Tc(NNMe₂)Cl(dppe)₂ ][PF₆ ] (0.12 mmol, 29%).

For [Tc(N₂)(dppe)₂ Cl]

Analysis calculated for C₅₂ H₄₈ ClN₂ P₄ Tc: 65.17% C; 5.05% H; 2.92% N.Found: 64.70% C; 5.32% H; 2.07% N.

For [Tc(NNMe₂)Cl(dppe)₂ ][PF₆ ]

Analysis calculated for C₅₄ H₅₂ ClF₆ P₅ Tc: 57.33% C; 4.63% H; 2.48% N.Found: 51.6% C; 4.4% H; 1.8% N.

Method 2

A reaction solution was prepared as for Method 1 from 95 mg [NBu₄][TcOCl₄ ] (0.19 mmol), 27 μl Me₂ NNH₂ (0.36 mmol), 333 mg dppe (0.84mmol) in 5 cm³ MeOH. This reaction mixture was stirred at roomtemperature for 70 hours. The reaction solution was filtered to removeexcess dppe (no yellow precipitate was observed), 65 mg NH₄ PF₆ (0.40mmol) was added to the filtrate as a solid and the solution was thenconcentrated in vacuo and the residue was taken up in 5 cm³ CH₂ Cl₂.This solution was filtered to remove undissolved inorganic salts. Afterfiltration, 25 cm³ ^(i) PrOH was added to the filtrate to give 135 mg ofa yellow-brown solid which was collected, washed and dried. This wasidentified by comparison of the IR spectrum of this complex with that of[Tc(NNMe₂)Cl(dppe)₂ ][PF₆ ] prepared by Method 1 (0.12 mmol, 63%).

EXAMPLE 15 The Reaction of [NBu₄ ][TcOBr₄ ], Me₂ NNH₂ and dppe

This was performed by Method 1 for the reaction described above for[NBu₄ ][TcOCl₄ ] using 130 mg [NBu₄ ][TcOBr₄ ] (0.20 mmol), 20 μl Me₂NNH₂ (0.26 mmol), 247 mg dppe (0.62 mmol) in 5 cm³ MeOH. This gave 55 mgof a yellow complex, Tc(N₂)Br(dppe)₂ (0.06 mmol, 30%). No salts wereisolated from the reaction filtrate after the addition of an excess ofNH₄ PF₆ to the solution. Analysis calculated for C₅₂ H₄₈ BrN₂ P₄ Tc:62.22% C; 4.82% H; 2.79% N. Found: 58.48% C; 4.71% H; 2.03% N.

^(99m) Tc Complexes

General: The ^(99m) Tc diazenide and hydrazide (2-) complexes wereprepared in a straightforward fashion from the appropriate hydrazine,^(99m) TcO₄ ⁻ and a suitable ligand. The complex preparations were foundto yield the desired cationic products in reasonably high radiochemicalpurity (see Tables 2-4). The main contaminants in these preparationswere the [Tc^(III) Cl₂ (L)₂ ]⁺ cations, as verified by comparison ofHFLC and TLC characteristics of these impurities with authentic samplesof these Tc^(III) species prepared by a literature method.²² There issome question in the case of the MePhNNH₂ labelled species whether thecomplexes formed are of the formulation [Tc^(IV) (NNMePh)Cl(L)₂ ]⁺ or[Tc^(V) (NH)O(L)₂ ]⁺. Recent ICES studies on the preparation obtainedfrom the labelling where L=P65 (mmmpe) have shown that the oxidationstate of the complex obtained is +4.²³ This indicates that the speciespresent in the MePhNNH₂ preparations are the desired hydrazido (2-)species.

Reagents: The ligands used are given in Table 1. All other reagents usedwere from commercial suppliers and used as received. [^(99m) TcO₄ ]⁻ wasobtained as solutions in physiological saline from Amertec IIgenerators. Reaction products were analyzed by HPLC, TLC and gelelectrophoresis as described elsewhere.²⁴ All preparations wereperformed under an atmosphere of nitrogen gas.

EXAMPLE 16

Complex Preparation: 20-25 μl of hydrazine was added to 2 cm³ ofabsolute ethanol, then ^(99m) TcO₄ ⁻ (0.2-3.0 GBq) and 10 mg of ligandwere added to the solution. This mixture was heated to 120° C. for 30-60minutes, cooled to room temperature and analyzed. For biodistributionstudies the total volume of the preparation was made up to 5 cm³ by theaddition of sterile saline solution.

Animal Biodistribution Studio: Six male Sprague Dawley rats wereinjected while under light ether anaesthesia with 0.1 cm³ of preparation(i.v., tail vein) and half were sacrificed by cervical dislocation whileunder ether anaesthesia at the appropriate time interval post-injectionand dissected. Organs were weighed and their activities measured in anionisation chamber. For the purposes of calculations blood was assumedto constitute 5.8% of the total body weight, muscle was assumed to be43% and the lungs were assumed to weigh 1 g.

Biodistribution results are given in Tables 2-4.

                                      TABLE 1                                     __________________________________________________________________________    Ligands used in .sup.99m Tc labelling work                                    Abbreviation                                                                         Structure                      Name                                    __________________________________________________________________________    dmpe                                                                                  ##STR11##                     1,2-bis(dimethylphenylphosphino)etha                                          ne                                      dppe                                                                                  ##STR12##                     1,2-bis(diphenylphosphino)ethane        P56                                                                                   ##STR13##                                                                                                    ##STR14##                              PL28                                                                                  ##STR15##                     bis((dimethylphosphino)methyl)ether                                           7                                       P46                                                                                   ##STR16##                                                                                                    ##STR17##                              PL34                                                                                  ##STR18##                                                                                                    ##STR19##                              PL38                                                                                  ##STR20##                                                                                                    ##STR21##                              PL31                                                                                  ##STR22##                     bis((diethlylphosphino)methyl)ether                                           .                                       P53                                                                                   ##STR23##                                                                                                    ##STR24##                              P65                                                                                   ##STR25##                                                                                                    ##STR26##                              PL37                                                                                  ##STR27##                                                                                                    ##STR28##                              PL40                                                                                  ##STR29##                                                                                                    ##STR30##                              PL42                                                                                  ##STR31##                                                                                                    ##STR32##                              PL43                                                                                  ##STR33##                                                                                                    ##STR34##                              PL46                                                                                  ##STR35##                                                                                                    ##STR36##                              PL49                                                                                  ##STR37##                                                                                                    ##STR38##                              PL50                                                                                  ##STR39##                                                                                                    ##STR40##                              P68                                                                                   ##STR41##                                                                                                    ##STR42##                              __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    Biodistributions of Phenyldiazenide .sup.99m Tc species in                    __________________________________________________________________________    Rats                                                                          Notebook                                                                             IV23          VI12          VI9                                        Ligand dmpe          PL28          P46                                           MEK 60            84            80                                         RCP (%)                                                                          HPLC                                                                              40            70            75                                         Time P.I.                                                                            2      60     2      60     2      60                                  __________________________________________________________________________    Heart  0.91                                                                             (14)                                                                              0.78                                                                             (03)                                                                              1.12                                                                             (11)                                                                              0.65                                                                             (06)                                                                              0.96                                                                             (04)                                                                              0.80                                                                             (02)                             Blood  6.98                                                                             (71)                                                                              1.10                                                                             (02)                                                                              4.18                                                                             (05)                                                                              0.46                                                                             (04)                                                                              7.45                                                                             (63)                                                                              1.01                                                                             (16)                             Muscle 22.8                                                                             (3.0)                                                                             14.0                                                                             (3.7)                                                                             30.2                                                                             (3.0)                                                                             27.4                                                                             (3.6)                                                                             21.4                                                                             (3.1)                                                                             17.0                                                                             (4.0)                            Lung   1.88                                                                             (14)                                                                              0.86                                                                             (10)                                                                              1.18                                                                             (14)                                                                              0.62                                                                             (05)                                                                              1.41                                                                             (27)                                                                              0.36                                                                             (05)                             Liver  22.2                                                                             (2.6)                                                                             10.5                                                                             (8) 17.8                                                                             (2.9)                                                                             5.95                                                                             (57)                                                                              26.0                                                                             (1.0)                                                                             6.92                                                                             (1.23)                           S.I.   13.2                                                                             (8) 36.7                                                                             (4) 13.2                                                                             (1.0)                                                                             39.6                                                                             (2.7)                                                                             11.0                                                                             (3.2)                                                                             44.0                                                                             (1.9)                            Kidney 11.2                                                                             (8) 9.91                                                                             (1.25)                                                                            9.41                                                                             (0.30)                                                                            5.90                                                                             (06)                                                                              9.62                                                                             (48)                                                                              2.88                                                                             (16)                             Bladder                                                                              0.11                                                                             (03)                                                                              11.3                                                                             (4) 0.11                                                                             (06)                                                                              10.9                                                                             (5.9)                                                                             0.11                                                                             (05)                                                                              17.8                                                                             (2.6)                            & Urine                                                                       Brain  0.06                                                                             (01)                                                                              0.02                                                                             (01)                                                                              0.04                                                                             (00)                                                                              0.02                                                                             (00)                                                                              0.05                                                                             (01)                                                                              0.01                                                                             (00)                             H/Bl   1.97                                                                             (05)                                                                              9.52                                                                             (33)                                                                              3.97                                                                             (32)                                                                              21.3                                                                             (0.8)                                                                             2.05                                                                             (29)                                                                              13.2                                                                             (2.1)                            H/Li   0.54                                                                             (11)                                                                              0.93                                                                             (11)                                                                              0.82                                                                             (19)                                                                              1.56                                                                             (12)                                                                              0.58                                                                             (06)                                                                              1.79                                                                             (30)                             __________________________________________________________________________    Notebook                                                                             VI31          LH2.17        LH2.30                                     Ligand P46 (HPLC purified)                                                                         PL42          PL43                                          MEK 50            65            26                                         RCP (%)                                                                          HPLC                                                                              50            70            50                                         Time P.I.                                                                            2      60     2      60     2      60                                  __________________________________________________________________________    Heart  1.05                                                                             (09)                                                                              0.96                                                                             (04)                                                                              1.22                                                                             (30)                                                                              1.19                                                                             (20)                                                                              0.55                                                                             (03)                                                                              0.26                                                                             (03)                             Blood  7.00                                                                             (0.31)                                                                            0.78                                                                             (08)                                                                              28.6                                                                             (1.4)                                                                             8.99                                                                             (2.28)                                                                            21.5                                                                             (3.5)                                                                             1.14                                                                             (36)                             Muscle 21.0                                                                             (3.1)                                                                             21.3                                                                             (2.3)                                                                             18.1                                                                             (0.5)                                                                             21.3                                                                             (0.3)                                                                             21.7                                                                             (2.4)                                                                             10.9                                                                             (1.3)                            Lung   1.33                                                                             (14)                                                                              0.47                                                                             (05)                                                                              2.56                                                                             (33)                                                                              1.57                                                                             (32)                                                                              1.47                                                                             (04)                                                                              0.22                                                                             (03)                             Liver  22.1                                                                             (2.0)                                                                             4.94                                                                             (77)                                                                              22.8                                                                             (3.2)                                                                             14.7                                                                             (1.6)                                                                             21.4                                                                             (1.6)                                                                             9.08                                                                             (2.03)                           S.I.   11.5                                                                             (3.2)                                                                             39.8                                                                             (0.3)                                                                             7.66                                                                             (18)                                                                              31.8                                                                             (2.0)                                                                             8.6                                                                              (0.5)                                                                             45.6                                                                             (6.8)                            Kidney 11.1                                                                             (2.1)                                                                             3.31                                                                             (17)                                                                              5.35                                                                             (46)                                                                              3.52                                                                             (47)                                                                              9.19                                                                             (74)                                                                              2.32                                                                             (32)                             Bladder                                                                              1.01                                                                             (1.49)                                                                            17.0                                                                             (4.3)                                                                             0.06                                                                             (01)                                                                              2.61                                                                             (23)                                                                              0.16                                                                             (06)                                                                              25.4                                                                             (4.6)                            & Urine                                                                       Brain  0.04                                                                             (00)                                                                              0.01                                                                             (00)                                                                              --     --     --     --                                  H/Bl   2.37                                                                             (12)                                                                              18.9                                                                             (1.6)                                                                             0.59                                                                             (12)                                                                              2.13                                                                             (43)                                                                              0.41                                                                             (06)                                                                              3.83                                                                             (1.03)                           H/Li   0.66                                                                             (12)                                                                              2.77                                                                             (36)                                                                              0.73                                                                             (24)                                                                              1.12                                                                             (26)                                                                              0.38                                                                             (03)                                                                              0.40                                                                             (03)                             __________________________________________________________________________    Notebook                                                                             LH2.51        PAH1.26       VI28                                       Ligand P65           PL50          PL38                                          MEK 60            70            86                                         RCP (%)                                                                          HPLC                                                                              85            75            80                                         Time P.I.                                                                            2      60     2      60     2      60                                  __________________________________________________________________________    Heart  1.20                                                                             (11)                                                                              1.08                                                                             (09)                                                                              0.83                                                                             (09)                                                                              0.65                                                                             (04)                                                                              1.04                                                                             (06)                                                                              0.65                                                                             (09)                             Blood  5.73                                                                             (58)                                                                              1.05                                                                             (09)                                                                              4.38                                                                             (25)                                                                              0.42                                                                             (03)                                                                              4.51                                                                             (1.36)                                                                            0.16                                                                             (02)                             Muscle 27.8                                                                             (8.4)                                                                             23.6                                                                             (7.7)                                                                             18.7                                                                             (2.5)                                                                             14.9                                                                             (2.7)                                                                             21.0                                                                             (5.1)                                                                             16.2                                                                             (4.1)                            Lung   1.61                                                                             (18)                                                                              0.53                                                                             (08)                                                                              1.02                                                                             (12)                                                                              0.43                                                                             (06)                                                                              1.41                                                                             (13)                                                                              0.35                                                                             (11)                             Liver  22.0                                                                             (1.8)                                                                             6.68                                                                             (1.19)                                                                            34.8                                                                             (1.2)                                                                             4.35                                                                             (30)                                                                              28.4                                                                             (1.6)                                                                             9.27                                                                             (35)                             S.I.   11.2                                                                             (2.1)                                                                             39.8                                                                             (4.3)                                                                             12.8                                                                             (0.7)                                                                             57.9                                                                             (2.4)                                                                             11.5                                                                             (2.0)                                                                             57.0                                                                             (2.8)                            Kidney 12.0                                                                             (1.2)                                                                             3.71                                                                             (07)                                                                              12.0                                                                             (0.30)                                                                            6.81                                                                             (56)                                                                              10.7                                                                             (1.9)                                                                             4.01                                                                             (44)                             Bladder                                                                              0.11                                                                             (0.05)                                                                            9.95                                                                             (66)                                                                              0.09                                                                             (03)                                                                              6.76                                                                             (65)                                                                              0.14                                                                             (04)                                                                              5.81                                                                             (1.46)                           & Urine                                                                       Brain  --     --     --     --     0.03                                                                             (00)                                                                              0.00                                                                             (00)                             H/Bl   3.33                                                                             (30)                                                                              15.8                                                                             (1.0)                                                                             2.68                                                                             (22)                                                                              22.2                                                                             (0.4)                                                                             3.59                                                                             (88)                                                                              62.5                                                                             (7.0)                            H/Li   0.81                                                                             (12)                                                                              2.33                                                                             (32)                                                                              0.31                                                                             (04)                                                                              1.27                                                                             (96)                                                                              0.48                                                                             (01)                                                                              1.05                                                                             (17)                             __________________________________________________________________________

                  TABLE 3                                                         ______________________________________                                        Biodistributions of [Tc.sup.III (NNC.sub.6 H.sub.4 NO.sub.2)(Cl(dmpe).sub.    2 ].sup.+ in Rats                                                             ______________________________________                                        Notebook      CMAIV78                                                         Ligand        dmpe                                                               MEK        86                                                              RCP (%)                                                                          HPLC       65                                                              Time P.I.     2                60                                             ______________________________________                                        Heart         1.15   (22)      0.67 (05)                                      Blood         5.68   (66)      0.92 (07)                                      Muscle        26.2   (7.7)     16.8 (1.2)                                     Lung          2.27   (15)      1.04 (23)                                      Liver         22.4   (3.9)     12.3 (0.7)                                     S.I.          13.0   (3.1)     33.8 (3.2)                                     Kidney        9.47   (25)      9.47 (33)                                      Bladder       0.08   (02)      7.28 (1.10)                                    & Urine                                                                       Brain         0.12   (00)      0.06 (00)                                      H/Bl          3.00   (49)      11.0 (0.9)                                     H/Li          0.72   (28)      0.76 (12)                                      ______________________________________                                    

                                      TABLE 4                                     __________________________________________________________________________    Biodistributions of .sup.99m Tc-hydrazide (2-) species in Rats and Guinea     Pigs                                                                          __________________________________________________________________________    Notebook                                                                             PAH2.14      CMAIV58      CHAV141                                      Ligand P65          dmpe         dmpe (HPLC purified)                            MEK 86           78           83                                           RCP (%)                                                                          HPLC                                                                              90           70           73                                           Time P.I.                                                                            2      60    2      60    2      60                                    __________________________________________________________________________    Heart  0.95                                                                             (09)                                                                              0.69                                                                             (03)                                                                             1.13                                                                             (13)                                                                              0.80                                                                             (08)                                                                             1.25                                                                             (08)                                                                              0.99                                                                             (15)                               Blood  4.77                                                                             (10)                                                                              0.69                                                                             (13)                                                                             7.84                                                                             (47)                                                                              1.05                                                                             (11)                                                                             7.95                                                                             (21)                                                                              1.05                                                                             (21)                               Muscle 26.1                                                                             (5.8)                                                                             20.2                                                                             (2.7)                                                                            27.9                                                                             (4.9)                                                                             20.6                                                                             (3.2)                                                                            26.3                                                                             (5.2)                                                                             19.3                                                                             (4.9)                              Lung   1.58                                                                             (0.36)                                                                            0.33                                                                             (02)                                                                             2.36                                                                             (37)                                                                              1.14                                                                             (07)                                                                             2.40                                                                             (0.21)                                                                            1.28                                                                             (20)                               Liver  22.8                                                                             (1.4)                                                                             9.23                                                                             (26)                                                                             22.2                                                                             (0.6)                                                                             11.6                                                                             (1.6)                                                                            21.1                                                                             (1.7)                                                                             10.8                                                                             (1.9)                              S.I.                10.5                                                                             (2.2)                                                                             30.6                                                                             (3.4)                                                                            11.9                                                                             (3.2)                                                                             31.1                                                                             (4.5)                              Kidney 7.76                                                                             (12)                                                                              1.95                                                                             (15)                                                                             9.95                                                                             (1.40)                                                                            11.1                                                                             (0.4)                                                                            10.8                                                                             (0.6)                                                                             11.6                                                                             (1.3)                              Bladder             0.08                                                                             (01)                                                                              6.84                                                                             (77)                                                                             0.12                                                                             (07)                                                                              4.70                                                                             (93)                               & Urine                                                                       Brain               0.05                                                                             (01)                                                                              0.03                                                                             (01)                                                                             0.07                                                                             (01)                                                                              0.04                                                                             (01)                               H/Bl   3.25                                                                             (27)                                                                              15.0                                                                             (3.4)                                                                            2.43                                                                             (12)                                                                              12.2                                                                             (1.4)                                                                            2.27                                                                             (21)                                                                              14.2                                                                             (2.4)                              H/Li   0.64                                                                             (06)                                                                              1.11                                                                             (02)                                                                             0.78                                                                             (13)                                                                              1.06                                                                             (13)                                                                             0.82                                                                             (04)                                                                              1.30                                                                             (41)                               __________________________________________________________________________    Notebook CMAVI15        CMAVI36       CMAVI36                                 Ligand   P46            P46* (HPLC purified)                                                                        P46 (HPLC                                                                     purified)                                                                     RATS                                       MEK   64             54            54                                      RCP (%)                                                                          HPLC  65             53            53                                      Time P.I.                                                                              2       60     2      60     60                                      __________________________________________________________________________    Heart    0.81                                                                             (07) 0.58                                                                             (04)                                                                              0.96                                                                             (12)                                                                              0.65                                                                             (03)                                                                              0.97                                                                             (06)                                 Blood    7.10                                                                             (0.51)                                                                             0.50                                                                             (05)                                                                              10.1                                                                             (1.7)                                                                             0.89                                                                             (12)                                                                              0.27                                                                             (02)                                 Muscle   28.4                                                                             (2.5)                                                                              18.4                                                                             (2.5)                                                                             21.9                                                                             (3.3)                                                                             28.5                                                                             (2.2)                                                                             20.0                                                                             (1.2)                                Lung     1.33                                                                             (09) 0.30                                                                             (07)                                                                              1.30                                                                             (05)                                                                              0.51                                                                             (11)                                                                              0.36                                                                             (10)                                 Liver    23.3                                                                             (0.5)                                                                              7.23                                                                             (70)                                                                              15.9                                                                             (1.1)                                                                             5.18                                                                             (36)                                                                              8.29                                                                             (67)                                 S.I.     9.38                                                                             (3.20)                                                                             44.8                                                                             (2.6)                                                                             11.3                                                                             (1.2)                                                                             15.0                                                                             (7.1)                                                                             43.6                                                                             (2.2)                                Kidney   9.37                                                                             (52) 2.13                                                                             (10)                                                                              13.0                                                                             (1.6)                                                                             11.0                                                                             (0.3)                                                                             4.05                                                                             (66)                                 Bladder  0.18                                                                             (10) 19.2                                                                             (1.6)                                                                             0.22                                                                             (17)                                                                              10.6                                                                             (1.1)                                                                             12.7                                                                             (1.0)                                & Urine                                                                       Brain    0.04                                                                             (02) 0.51                                                                             (13)                                                                              --     --     --                                      H/Bl     1.65                                                                             (08) 16.5                                                                             (1.0)                                                                             2.89                                                                             (53)                                                                              17.8                                                                             (2.1)                                                                             58.7                                                                             (1.0)                                H/Li     0.48                                                                             (03) 1.01                                                                             (13)                                                                              0.88                                                                             (10)                                                                              1.89                                                                             (0.22)                                                                            1.68                                                                             (14)                                 __________________________________________________________________________     *In Guinea Pig                                                           

EXAMPLES 17-19

All reactions were performed under an atmosphere of dinitrogen usingpredried, distilled solvents unless noted otherwise. [Bu₄ N][TcOCl₄ ]was prepared by the literature procedure.²⁸

EXAMPLE 17 Technetium Diazenido--Starting Materials

a) [TcCl(NNC₆ H₄ Cl)₂ (PPh₃)₂ ] 9

Method 1. From [Bu₄ N][TcOCl₄ ]

[Bu₄ N][TcOCl₄ ] (0.134 g, 0.268 mmol), 4-ClC₆ H₄ NHNH₂.HCl (0.120 g,0.67 mmol, 2.5 equivalents), Et₃ N (0.09 ml, 0.67 mmol), and PPh₃ (0.211g, 0.804 mmol, 3 equivalents) in dry methanol (5 ml were stirred for 2hours at room temperature. The khaki solid was collected by filtration,washed with methanol and ether and dried. (yield 0.134 g, 53%). Theproduct could be recrystallised from CH₂ Cl₂ /MeOH yielding brightorange crystals. (Found: C,61.23; H,3.98; N,6.05; Cl,11.74. TcC₄₈ H₃₈ N₄P₂ Cl₃ requires C,61.45; H,4.08; N,5.97; Cl,11.34%). HPLC retention time9.4 minutes, single species. v_(max). (KBr plates, nujol mull) 1600,1555 cm⁻¹ (NN). ³¹ P NMR (CDCl₃) 30.27 ppm singlet.

Method 2. From [NH₄ ][TcO₄ ]

Aqueous [NH₄ ][TcO₄ ] (0.5 ml, 0.181 mmol) was evaporated to dryness invacuo. ClC₆ H₄ NHNH₂.HCl (0.142 g, 0.793 mmol) in dry methanol (2.5 ml)was added with stirring to give an orange solution after 10 minutes.Solid PPh₃ (0.204 g, 0.778 mmol) was added and the mixture heated underreflux for 1.5 hours. After cooling to room temperature the khaki solidwas collected by filtration and washed with ether (yield 0.113 g, 67%).The product could be crystallised from CH₂ Cl₂ /MeOH to yield an orangecrystalline solid which has an identical IR spectrum to an authenticsample of 9 prepared from [TcOCl₄ ]⁻.

b) [Tc(NNC₆ H₄ CH₃)₂ (PPh₃)₂ ] 10

[Bu₄ N][TcOCl₄ ] (0.178 g, 0.356 mmol), CH₃ C₆ H₄ NHNH₂.HCl (0.282 g,1.78 mmol, 5 equivalents), Et₃ N (0.25 ml, 1.78 mmol), and PPh₃ (0.280g, 1.07 mmol, 3 equivalents) were stirred in dry methanol (5 ml)overnight to give a khaki suspension. The product was collected byfiltration, washed with ether and dried (yield 0.122 g, 40%). HPLCretention time 10.4 minutes, one major species. Analysis on the crudematerial gave (Found: C,64.1; H,4.6; N,5.9; Cl,3.53. TcC₅₀ H₄₄ N₄ P₂ Clrequires C 66.93; H 4.94; N 6.24; Cl, 3.95%) ¹ H NMR (CDCl₃) 2.29[6H, s,2×CH₃ ], 6.5-8.0 [38H, m, phenyl H]. ³¹ P NMR (CDCl₃) 28.6 ppm singlet.v_(max). 1620, 1570, 1535 cm⁻¹ (NN). The product may be recrystallisedfrom CH₂ Cl₂ /MeOH.

c) [TcCl₂ (NNC₆ H₄ NO₂) (PPh₃)₂ ] 11

[Bu₄ N[TcOCl₄ ] (0.152 g, 0.304 mmol), O₂ NC₆ H₄ NHNH₂ (0.116 g, 0.76mmol, 2.5 equivalents), and PPh₃ (0.239 g, 0.912 mmol, 3 equivalents) indry methanol (5 ml) were stirred overnight to give a pale orange solidwhich was collected by filtration (yield 0.223 g, 77%). This wasrecrystallised from CH₂ Cl₂ /MeOH to give a lime-green solid (0.151 g,52%). v_(max). 1620, 1600 (NN), 1555 (NO₂), 1335 (NO₂) cm⁻¹. ¹ H NMR(CDC₃) 3.4 [MeOH], 7.0-8.0[phenyl H]. ³¹ P NMR (CDCl₃) 30.0 ppm singlet.HPLC retention time 10.4 minutes. (Found: C,57.65; H,4.18; N,4.94;Cl,8.60. Found: C,57.42; H,4.24; N,4.95; Cl,7.95. TcC₄₃ H₃₈ N₃ Cl₂ P₃ P₂requires C,58.92; H, 4.37; N, 4.79; Cl,8.09%).

EXAMPLE 18 Substitution Chemistry of the Technetium Diazenido--StartingMaterials

a) [TcCl(NNC₆ H₄ Cl)(dppe)₂ ][BPh₄ ] 12

9 (0.098 g, 0.104 mmol) and dppe (0.104 g, 0.26 mmol, 2.5 equivalents)in methanol-toluene (1:1, 4 ml) were heated under reflux for 3 hours togive a dark orange solution. Solid NaBPh₄ (0.035 g, 1 equivalent) wasadded with stirring to precipitate an orange solid. The product wascollected by filtration (yield 0.117 g, 77%). The crude product could berecrystallised from CH₂ Cl₂ /ether. (Found: C,70.55; H,5.34; N,2.17;Cl,4.72. TcC₈₀ H₇₂ N₂ BP₄ Cl₂ requires C,70.34; H,5.31; N,2.05;Cl,5.19%). HPLC retention time 14 minutes. v_(max). 1575, 1665 cm⁻¹(NN). ¹ H NMR (CDCl₃) 2.68[8H, broad m, 2×--CH₂ CH₂ --], 6.5-7.5[64H,broad unresolved m, phenyl H].

b) [TcCl(NNC₆ H₄ Cl)(dppe)₂ ][PF₆ ] 12a

This was prepared in an analogous fashion to 12 using 9 (0.101 g, 0.107mmol) and dppe (0.107 g, 0.269 mmol) in methanol/toluene (1:1, 4 ml)under reflux for 1 hour. [NH₄ ][PF₆ ] (0.018 g, 0.110 mmol) was addedwith stirring to the filtered reaction mixture to give 12a (yield 0.059g, 43%). This could be recrystallised from CH₂ Cl₂ /MeOH (Found:C,55.44; H,4.27; N,2.48; Cl,6.35. TcC₅₈ H₄₄ N₂ P₅ Cl₂ F₆ requiresC,57.68; H,3.67; N,2.32; Cl,5.87%).

c) [TcCl(NNC₆ H₄ NO₂)(dppe)₂ ][BPh₄ ] 13

11 (0.051 g, 0.06 mmol) and dppe (0.060 g, 0.151 mmol, 2.5 equivalents)in methanol/toluene (1:1, 3 ml) were heated under reflux for 1 hour togive an orange-red solution. After cooling to room temperature solidNaBPh₄ (0.02 g, 1 equivalent) was added with stirring to precipitate theproduct as an orange solid. This was collected by filtration and washedwith MeOH and Et₂ O (yield 0.06 g, 72%). The product was recrystallisedfrom CH₂ Cl₂ /Et₂ O (yield 0.042 g, 50%) as an orange crystalline solid.v_(max). 1645s, 1600w (NN), 1570 (NO₂), 1340 (NO'₂) cm⁻¹. HPLC retentiontime 14.2 minutes, single peak. (Found: C,67.65; H,5.12; N,2.93;Cl,4.14. TcC₈₂ H₇₂ N₃ O₂ ClP₄ B. 1/2CH₂ Cl₂ requires C,68.66; H,5.10;N,2.91; Cl,4.91%).

d) [Tc(NNC₆ H₄ Cl)(S₂ CNMe₂)(PPh₃)] 14

9 (0.139 g, 0.148 mmol) and NaS₂ CNMe₂ (0.08 g, 0.444 mmol, 3equivalents) in absolute ethanol (2 ml) were heated under reflux for 1.5hours. The orange solid was collected by filtration after cooling (yield0.072 g) and redissolved in CH₂ Cl₂ before passage down a Fluorsilcolumn eluting the orange band with CH₂ Cl₂. This eluate was evaporatedto dryness and the residue recrystallised from CH₂ Cl₂ /Et₂ O to givedark orange crystals (yield 0.072 g, 66%). HPLC retention time 13.6minutes, single species. (Found: C,45.82; H,4.09; N,6.79; Cl,6.25.Found: C,45.99; H,4.04; N,6.77. TcC₃₀ H₃₁ N₄ ClS₄ P. 1/2CH₂ Cl₂ requiresC,46.74; H,4.11, N, 7.15; Cl,9.05. TcC₃₀ H₃₁ N₄ ClS₄ P. 1/4CH₂ Cl₂requires C,47.65; H,4.16, N,7.35; Cl, 6.97%). ¹ H NMR (CDCl₃) 2.92[3H,s, CH₃ ], 3.06[3H, s, CH₃ ], 3.31[3H, s, CH₃ ], 3.39[3H, s, CH₃ ],5.27[CH₂ Cl₂ ], 6.8-7.7[19H, m, phenyl H]. ³¹ P NMR (CDCl₃) no signalwas observed in this sample at room temperature.

e) [TcCl(NNC₆ H₄ Cl)(maltol)(PPh₃)₂ ] 15

9 (0.145 g, 0.155 mmol) and maltol (0.059 g, 0.465 mmol, 3 equivalents)in a absolute ethanol (2 ml) were heated under reflux for 2 hours. Aftercooling to room temperature the orange product was collected byfiltration and washed with ethanol. The product was recrystallised fromCH₂ Cl₂ /ether (yield 0.03 g, 21%) as dark orange crystals. (Found:C,59.68; H,4.11; N,3.03; Cl,7.73. TcC₄₈ H₃₉ N₂ Cl₂ O₃ P₂ requiresC,62.41; H,4.23; N,3.03, Cl,7.68%). v_(max). 1615s, 1560 cm⁻¹. ¹ H NMR(CDCl₃) 2.21[3H, s, CH₃ ], 5.63[1H, d, J³ _(HH) =4 Hz, C═CH], 6.92[1H,d, J³ _(HH) =4 Hz, C═CH], 7.0-8.0[34H, m phenyl H]. ³¹ P NMR (CDCl₃)30.0 ppm singlet. HPLC retention time 10 minutes.

f) [Tc(NNC₆ H₄ Cl)(salen)(PPh₃)] 16

9 (0.100 g, 0.107 mmol), salenH₂ (0.032 g, 0.119 mmol, 1.1 equivalents),and Et₃ N (0.40 ml, 0.259 mmol, 2.2 equivalents) in dry methanol/toluene(1:1, 3 ml) were heated under reflux for2 hours. After cooling, additionof ether gave a khaki-green solid which was collected by filtration,washed with ether and dried (yield 0.052 g, 63%). The product could berecrystallised from CH₂ Cl₂ /heptane as very dark green crystals.(Found: C,61.77; H,4.41; N, 7.17; Cl,4.77. TcC₄₀ H₃₃ N₄ PO₂ Cl requiresC,62.63; H,4.34; N,7.30; Cl,4.62%). v_(max). 1600, 1610, 1620 (NN), 1540(C═N) cm⁻¹. ¹ H NMR (CDCl₃) 4.0[4H, broad m, --CH₂ CH₂ --], 6.0-7.6[27H,broad m, phenyl H], 8.14[2H, s, N═CH]. ³¹ P NMR (CDCl₃) no signal wasobserved at room temperature. HPLC retention time 11.6 minutes.

g) [Tc(NNC₆ H₄ Cl)₂ (N₂ S₂)]_(x) 17 N₂ S₂ =(HSCH(Me)CONHCH₂ --)₂

9 (0.083 g, 0.088 mmol), N₂ S₂ (0.023 g, 0.097 mmol, 1.1 equivalents),and Et₃ N (0.05 ml, 0.34 mmol, 4 equivalents) in dry methanol (2 ml)were heated under reflux for 1 hour to give a dark brown-green solution.The solvent was removed in vacuo and the brown oil triturated withisopropanol to give a dark brown solid product (yield 0.011 g). Theproduct was too insoluble for satisfactory recrystallisation andanalysis by NMR, but appeared to be diamagnetic. HPLC retention time12.2 minutes. (Found: C,40.36; H,4.40; N,9.19; Cl,11.97. TcC₂₀ H₂₄ N₄Cl₂ S₂ O₂ requires C,40.96; H,4.12; N,9.55; Cl, 12.09%).

EXAMPLE 19 Technetium Imido Complexes

[TcCl₂ (NC₆ H₄ CO₂)(PPh₃)₂ ] 18

Method 1. From [NH₄ ][TcO₄ ]

Aqueous [NH₄ ][TcO₄ ] (1 ml, 0.343 mmol), 2-HO₂ CC₆ H₄ NH₃ Cl(2-carboxyaniline hydrochloride) (0.298 g, 1.715 mmol, 5 equivalents),and PPh₃ (0.360 g, 1.372 mmol, 4 equivalents) in reagent grade methanol(10 ml) were stirred overnight to give a bright green precipitate. Theproduct was collected by filtration, washed with MeOH, ether and driedin vacuo (yield 0.139 g, 50%). (Found: C,63.30; H,4.44; N, 1.77. TcC₄₃H₃₄ NO₂ P₂ Cl₂ requires C,62.33; H,4.14; N, 1.67%). The product wassoluble in DMF and CH₂ Cl₂.

Method 2. From [Bu₄ N][TcOCl₄ ]

[Bu₄ N][TcOCl₄ ] (0.262 g, 0.525 mmol), anthranilic acid (0.72 g, 5.25mmol, 10 equivalents), and PPh₃ (0.48 g 1.84 mmol 3 5 equivalents) inabsolute ethanol (20 ml) were heated under reflux for 2 hours. The hotsolution was filtered (air) and taken to dryness in vacuo. The residuewas then triturated with ether and the solid green product isolatedafter filtration was recrystallised from EtOH/hexane (yield 0.114 g,26%). ³¹ P NMR (DMSO) 31.2 ppm singlet.

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We claim:
 1. A complex of ^(99m) Tc of formula:

    L.sub.n Tc═NR, L.sub.n Tc--N═NY or L.sub.n Tc(--N═NY).sub.2

where L is a mono-dentate or multi-dentate organic ligand; n is 1, 2, 3or 4; R is C₁₋₁₀ aryl, alkyl, alkoxyalkyl, aminoalkyl or thioethergroup;or is the group ═-NR¹ R² ; Y is a C₁₋₁₀ aryl, alkyl, alkoxyalkyl,aminoalkyl or thioether group; R¹ and R² are H, an aliphatic or cyclicC₁₋₁₀ alkyl group or a C₁₋₁₀ aryl, alkoxyalkyl, aminoalkyl or thioethergroup; R¹ and R² may be the same or different provided that both are notH.
 2. The complex as claimed in claim 1, where L is selected fromphosphines and arsines of the formula:

    Q.sub.2 B(CD.sub.2).sub.n BQ.sub.2,

where Q is H, a C₁₋₁₀ aryl group or a C₁₋₁₀ alkyl or alkoxyalkyl group;B is P or As; (CD₂) is a methylene group which may be substituted by aC₁₋₁₀ alkyl or alkoxyalkyl group; n is 1, 2, 3 or
 4. 3. Aradiopharmaceutical which includes a complex as claimed in claim
 1. 4. Aradiopharmaceutical which includes a complex as claimed in claim
 2. 5. Amethod of preparing the complex of claim 1 which comprises condensing acompound selected from the group consisting of a hydrazine, amine,isocyanate, sulphinylamine or phosphinimine with the technetium-99mcomplex of an organic ligand, said technetium-99m complex containing atechnetium-oxo bond.
 6. A method of preparing the complex of claim 2which comprises condensing a compound selected from the group consistingof a hydrazine, amine, isocyanate, sulphinylamine or phosphinimine withthe technetium-99m complex of an organic ligand, said technetium-99mcomplex containing a technetium-oxo bond.
 7. A method of preparing thecomplex of claim 1 which comprises reacting a hydrazine or amine withthe technetium-99m complex of an organic ligand, said technetium-99mcomplex containing one or more technetium-halogen bonds.
 8. A method ofpreparing the complex of claim 2 which comprises reacting a hydrazine oramine with the technetium-99m complex of an organic ligand, saidtechnetium-99m complex containing one or more technetium-halogen bonds.